Ajouaou Yousra, Magnani Elena, Madakashira Bhavani, Jenkins Eleanor, Sadler Kirsten C
Program in Biology, New York University Abu Dhabi, Abu Dhabi P.O. 129188, United Arab Emirates.
Center for Genomics and Systems Biology (CGSB), New York University Abu Dhabi, Abu Dhabi P.O. 129188, United Arab Emirates.
Cancers (Basel). 2023 Apr 14;15(8):2302. doi: 10.3390/cancers15082302.
The ataxia-telangiectasia mutated () gene is activated in response to genotoxic stress and leads to activation of the tumor suppressor gene which induces either senescence or apoptosis as tumor suppressive mechanisms. Atm also serves non-canonical functions in the response to oxidative stress and chromatin reorganization. We previously reported that overexpression of the epigenetic regulator and oncogene Ubiquitin Like with PHD and Ring Finger Domains 1 (UHRF1) in zebrafish hepatocytes resulted in -dependent hepatocyte senescence, a small liver and larval lethality. We investigated the role of on UHRF1-mediated phenotypes by generating zebrafish mutants. adults were viable but had reduction in fertility. Embryos developed normally but were protected from lethality caused by etoposide or HO exposure and failed to fully upregulate Tp53 targets or oxidative stress response genes in response to these treatments. In contrast to the finding that Tp53 prevents the small liver phenotype caused by UHRF1 overexpression, mutation and exposure to HO further reduced the liver size in UHRF1 overexpressing larvae whereas treatment with the antioxidant N-acetyl cysteine suppressed this phenotype. We conclude that UHRF1 overexpression in hepatocytes causes oxidative stress, and that loss of further enhances this, triggering elimination of these precancerous cells, leading to a small liver.
共济失调毛细血管扩张症突变（Atm）基因在受到基因毒性应激时被激活，并导致肿瘤抑制基因的激活，该基因诱导衰老或凋亡作为肿瘤抑制机制。Atm在应对氧化应激和染色质重组中也发挥非经典功能。我们之前报道过，在斑马鱼肝细胞中表观遗传调节因子和癌基因泛素样含PHD和环指结构域1（UHRF1）的过表达导致依赖Atm的肝细胞衰老、肝脏变小和幼虫致死。我们通过生成斑马鱼Atm突变体来研究Atm在UHRF1介导的表型中的作用。Atm成年鱼是存活的，但生育力下降。胚胎发育正常，但受到依托泊苷或过氧化氢（HO）暴露引起的致死保护，并且在这些处理后未能完全上调Tp53靶标或氧化应激反应基因。与Tp53可预防UHRF1过表达引起的肝脏变小表型这一发现相反，Atm突变和HO暴露进一步减小了UHRF1过表达幼虫的肝脏大小，而用抗氧化剂N-乙酰半胱氨酸处理可抑制该表型。我们得出结论，肝细胞中UHRF1过表达会导致氧化应激，而Atm缺失会进一步增强这种应激，触发这些癌前细胞的清除，导致肝脏变小。
